Ramana Kota V, Willis Monte S, White Michael D, Horton Jureta W, DiMaio J Michael, Srivastava Deepak, Bhatnagar Aruni, Srivastava Satish K
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Circulation. 2006 Oct 24;114(17):1838-46. doi: 10.1161/CIRCULATIONAHA.106.630830. Epub 2006 Oct 9.
Sepsis is a systemic inflammatory response syndrome characterized by excessive production of inflammatory cytokines and cardiovascular collapse. Postreceptor signaling events that lead to stress responses and cytokine production are sensitive to redox changes and products of lipid peroxidation.
We tested the hypothesis that inflammatory signaling and cytokine generation during sepsis depend on the activity of the enzyme aldose reductase, which catalyzes the reduction of lipid peroxidation-derived aldehydes and their glutathione conjugates. The results of the present study show that pharmacological inhibition of aldose reductase by sorbinil or knockdown of the enzyme by small interfering RNA prevents the activation of nuclear factor-kappaB and the release of tumor necrosis factor-alpha from lipopolysaccharide-stimulated RAW264.7 or H9c2 cells. Increases in serum and cardiac cytokines in response to lipopolysaccharide challenge were suppressed by inhibition of aldose reductase. Treatment with sorbinil blunted the activation of protein kinase C, c-Jun NH2-terminal kinase, and p38, as well as phosphorylation of interleukin receptor-associated kinase, IkappaB-alpha, IkappaB kinase complex-alpha/beta, and phospholipase-gamma1 and -beta1. These changes were associated with decreased myocardial nuclear factor-kappaB and activating protein-1 activity, prostaglandin E2 production, induction of cyclooxygenase 2, and inducible nitric oxide synthase. Sorbinil treatment also induced functional recovery in myocardial fractional shortening in vivo and preserved contractile function of isolated perfused hearts. Inhibition of aldose reductase increased survival in mice injected with lethal doses of lipopolysaccharide.
The present demonstration that aldose reductase mediates endotoxin-induced inflammation and cardiomyopathy suggests that inhibition of this enzyme may be useful to attenuate maladaptive host responses and to treat acute cardiovascular dysfunction associated with endotoxic shock.
脓毒症是一种全身炎症反应综合征，其特征为炎症细胞因子过度产生和心血管功能衰竭。导致应激反应和细胞因子产生的受体后信号事件对氧化还原变化和脂质过氧化产物敏感。
我们检验了以下假设，即脓毒症期间的炎症信号传导和细胞因子生成取决于醛糖还原酶的活性，该酶催化脂质过氧化衍生醛及其谷胱甘肽共轭物的还原。本研究结果表明，用索比尼尔对醛糖还原酶进行药理抑制或用小干扰RNA敲低该酶，可防止脂多糖刺激的RAW264.7或H9c2细胞中核因子-κB的激活以及肿瘤坏死因子-α的释放。抑制醛糖还原酶可抑制脂多糖攻击后血清和心脏细胞因子的增加。用索比尼尔处理可减弱蛋白激酶C、c-Jun氨基末端激酶和p38的激活，以及白细胞介素受体相关激酶、IκB-α、IκB激酶复合物-α/β和磷脂酶-γ1及-β1的磷酸化。这些变化与心肌核因子-κB和激活蛋白-1活性降低、前列腺素E2生成减少、环氧合酶2和诱导型一氧化氮合酶的诱导减少有关。索比尼尔处理还可诱导体内心肌缩短分数的功能恢复，并保留离体灌注心脏的收缩功能。抑制醛糖还原酶可提高注射致死剂量脂多糖小鼠的存活率。
目前关于醛糖还原酶介导内毒素诱导的炎症和心肌病的证明表明，抑制该酶可能有助于减轻适应性不良的宿主反应，并治疗与内毒素休克相关的急性心血管功能障碍。
